Concept 37
Master genes control basic body plans.

I’m Christiane Nüsslein-Volhard and I’m Eric Wieschaus. We were interested in the genes involved in development, and how they work to change one egg cell into a complex organism. In the ‘70s, we started looking at development of the fruit fly, Drosophila melanogaster – which goes through several distinct stages of development. DROSOPHILA MELANOGASTER: EGG, LARVA, PUPA, ADULT We isolated many mutants that led to the death of the embryo. These all had developmental errors. Using these mutants, we found the genes that control early embryonic development. Although the fertilized egg initially shows no polarity, proteins in the egg soon establish the head-to-tail and top-to-bottom orientation of the embryo. Some proteins are expressed and concentrated in a gradient, highest in the head. Others are expressed only in the head, or in both the head and the tail of the embryo. Another set of proteins is expressed in a concentration gradient from ventral to dorsal. At any point in the embryo there is a different concentration and mix of proteins. These protein differences turn on specific embryonic genes needed for the next stage of development — segmentation. Fruit flies are made up of segments, and the embryonic genes establish the identity of these segments, whether it is a head, thoracic, or abdominal segment. First, the general regions of the head, thorax, and abdomen are mapped out with the expression of "gap" genes. In this example, Krüppel is a gap gene mainly expressed in the thoracic segments. Krüppel mutants are missing those segments. The gap genes express proteins that control the pair rule genes; these specify the formation of each body segment. In this example, the pair-rule gene fushi tarazu (ftz) is expressed in the boundaries between segments. ftz mutants are missing every other segment. The segments are further defined by segment polarity genes, which gives each segment an anterior/posterior orientation. engrailed is a segment polarity gene. In mutants, the posterior end of the segments is replaced by a mirror image of the anterior end. This whole process takes only a few hours – changing the amorphous egg into an embryo where every cell has an identity delegated by its place within a segment. This is important for the next stage of development. I'm Ed Lewis. I was interested in how body parts develop. For instance in a fruit fly, how do wings or legs or antenna know where and when to form? Nüsslein-Volhard and Wieschaus showed how body segments are defined in a Drosophila embryo. After metamorphosis, these segments become the various parts of the adult fruit fly. Each segment has specific structures. For example, antennae develop in a head segment and wings develop in a thoracic segment. I looked at homeotic genes that control the specialization of the segments. These genes determine what gets made and where. "Homeotic" describes the process where one body part becomes like another by assuming its identity. This is very clear in the first homeotic gene that I studied called Ultrabithorax (Ubx). Ubx mutants have two pairs of wings instead of one. Wings are usually made by thoracic segment #2. Neighboring segment #3 usually makes a pair of halteres, small wing-like structures used for balance. In Ubx mutants, segment #3 has been transformed to segment #2. Instead of halteres, there are now an extra pair of wings. Another striking example of a homeotic transformation is the Antennapedia (Antp) mutant. Too much Antp protein and the antennae in one of the head segments are transformed into legs – like those normally found in the second thoracic segment. So, the segments themselves are essentially the same because they have the potential to make the same types of structures. It's the correct expression of the homeotic genes that dictates which segments make a particular type of structure. Homeotic genes are found in clusters on chromosomes. The bithorax cluster includes Ultrabithorax and two other genes. These genes control the specialization of thoracic and abdominal segments and are laid out on the chromosome in the orientation that they are expressed in the embryo. The five genes in the Antennapedia cluster control the specialization of the head and thoracic segments and are laid out in the chromosome in the orientation they are expressed. All homeotic genes share a 180-base pair conserved region called a homeobox. This region codes for 60 amino acids. These 60 amino acids are part of the protein's DNA binding site. Sometimes, homeobox proteins bind to promoters and activate the genes that make body parts in the segments. In other cases, the homeobox proteins turn off genes. In Ultrabithorax, the UBX protein inhibits the expression of wing genes in segment #3. Remove the inhibition, and the fruit fly has an extra pair of wings. It is very likely that an early ancestor of the fruit fly had two pairs of wings, like bees and wasps do today; Ubx evolved to turn off formation of the second pair of wings in segment #3. Having evolved from multi-segmented organisms, it makes sense that today's Drosophila change only the things that need to be changed by turning on and off genes. This type of homeotic control is not just limited to fruit flies. Mammals also have homeotic genes called hox genes. It's harder to see mammals as having segments, but compare these embryonic pictures. There is a very clear correlation between the hox gene cluster and the orientation of expressed genes in the mouse embryo. And it is clear that hox genes do control the specialization of cells in mammals in much the same way that homeotic genes do in fruit flies.

The "Nobel" call woke Eric Wieschaus out of a sound sleep. The Nobel Committee didn't think the sleepy-sounding Wieschaus got the message. They actually urged Christiane Nüsslein-Volhard, friend and co-winner, to call and make sure Wieschaus understood the importance of the event.

How do organisms other than Drosophila develop? Does early embryonic development in mammals follow the same patterns
as in Drosophila?